tbuckley/cabot-search huggingface dataset:
PB2549: CO-EXISTENT COLD AGGLUTININ DISEASE AND CRYOGLOBULINAEMIA
Authors: Nicole Japzon, Jahanzaib Khwaja, Maria Gabriel, Kavin Raju, Vijith Rajaratnam, Ali Rismani, Charalampia Kyriakou, Shirley D’sa
Journal: HemaSphere (2023)

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Cold agglutinin disease (CAD) is a clonal IgM disorder of erythrocyte agglutination and complement-mediated haemolysis due to antibody binding optimally at 4°C. This may result in anaemia or circulatory symptoms (cold intolerance, acrocyanosis and thrombosis). Cryoglobulinaemia (CRYO) is defined by the presence of immunoglobulins which precipitate at temperatures below 37°C and redissolve on warming. Patients with IgM gammopathies may have associated type I or II cryoglobulinaemia due to monoclonal IgM protein. The symptoms of CAD and CRYO overlap, but the pathology and management has differences. In our specialist practice, we observed the co-existence of these disorders in notable numbers of patients. Aims: To review the prevalence of cryoglobulinaemia in a cohort of patients with CAD and delineate clinical features and outcomes. Methods: Cryoglobulin testing is performed on all new patients as a part of clinic screening in our specialist IgM clinic. We reviewed consecutive patients with CAD who were tested for cryoglobulinaemia from 2017-2022. Baseline characteristics, symptom burden and treatment details were collected. Results: 24 patients (11 male, 13 female) with a diagnosis of CAD who were tested for cryoglobulins were included. 15/24 (63%) had cryoglobulins detected on testing: the majority were IgM type I (n=12) and remaining type II (n=1) or polyclonal type III (n=3). Median time to cryoglobulin detection was 21 months (range 1-64) from CAD diagnosis. Median age at CAD diagnosis was 70 (range 41-81) years. 14/24 (58%) had circulatory symptoms (11 acrocyanosis, 3 digital ischaemia/gangrene); 7/24 (29%) had thromboses: 6/24 venous (DVT/PE) and 1/24 arterial (stroke). All patients with digital ischaemia/gangrene or stroke had plasma exchange as a part of initial management. Therapy for CAD included blood transfusions (19/24; 79%), erythropoietic stimulating agents (2/24; 8%), chemoimmunotherapy (15/24; 63%), complement inhibition (4/24; 17%). At a median follow up of 24 months (range 6-73 months) from CAD diagnosis, 2-year overall survival was 91% (95% CI 72-97). Conclusion: In our cohort of patients with CAD, there was a high proportion of co-existent cryoglobulinaemia, predominantly type I and a notable incidence of digital ischaemia/ gangrene. Screening for CRYO is recommended to identify patients with exceptionally severe circulatory symptoms as the use of PLEX may be indicated. - Totaln=24 Cryoglobulins detected n=15 No cryoglobulins detected n=9 Age at CAD diagnosis, yr 70 (41-81) 71 (41-76) 66 (48-81) Haemoglobin at diagnosis, g/l 92 (44-124) 87 (60-124) 97 (48-123) Venous thrombosis 7 (29) 5 (33) 2 (22) Arterial thrombosis 1 (4) 1 (6) 0 Acrocyanosis 11 (46) 8 (53) 3 (33) Digital ischaemia/gangrene 3 (13) 3 (20) 0 Keywords: AIHA (see autoimmune hemolytic anemia)
Real-world Accuracy of CGM in Inpatient Critical and Noncritical Care Settings at a Safety-Net Hospital
Authors: Erin Finn, Lindsay Schlichting, Laura Grau, Ivor S. Douglas, Rocio I. Pereira
Journal: Diabetes Care (2023)

OBJECTIVE We sought to determine real-world accuracy of inpatient continuous glucose monitoring (CGM) at multiple levels of acuity in a large safety-net hospital. RESEARCH DESIGN AND METHODS We analyzed records from hospitalized patients on Dexcom G6 CGM, including clinical, point of care (POC), and laboratory (Lab) glucose, and CGM data. POC/Lab values were matched to the closest timed CGM value. Encounters were divided into not critically ill (NCI) versus critically ill (CI). CGM accuracy was evaluated. RESULTS Paired readings (2,744 POC-CGM; 3,705 Lab-CGM) were analyzed for 233 patients with 239 encounters (83 NCI, 156 CI). POC-CGM aggregated and average mean absolute relative differences (MARD) were 15.1% and 17.1%. Lab-CGM aggregated and average MARDs were 11.4% and 12.2%. Accuracy for POC-CGM and Lab-CGM was 96.5% and 99.1% in Clarke Error Grid zones A/B. CONCLUSIONS Real-world accuracy of inpatient CGM is acceptable for NCI and CI patients. Further exploration of conditions associated with lower CGM accuracy in real-world settings is warranted.
PB2479: ELTROMBOPAG, BUT NOT AVATROMBOPAG, REGULATES BONE MARROW MICROENVIRONMENT MIMICKING APLASTIC ANEMIA THROUGH DOWN-REGULATION OF FERROPTOSIS INHIBITOR
Authors: Jiang Ji, Shuqing Wang, Huiwen He, Yuan Yang, Qinglin Hu, Wanshu Chen, Miao Chen, Bing Han
Journal: HemaSphere (2023)

Topic: 23. Hematopoiesis, stem cells and microenvironment Background: Abnormal bone marrow microenvironment and over-secretion of interferon-γ were involved in pathogenesis of aplastic anemia (AA). Eltrombopag (EPAG) was an iron chelator which was known to be effective in treating AA. Whether EPAG participates in the regulation of AA patient’s bone marrow microenvironment is yet unknown. Aims: To explore the possible effects of EPAG on the bone marrow mesenchymal stem cells (BM-MSC) in the environment mimicking AA’s bone marrow microenvironment. Methods: Human BM-MSC cell line HS-5 was incubated with EPAG, avatrombopag (AVA) alone or together with IFN-γ. Cells incubated with IFN-γ only were taken as a model of AA’s bone marrow microenvironment. Cells incubated in blank complete medium were taken as normal control. Cell proliferation were detected by CCK-8 assay, and proportion of cell apoptosis were detected by cell flowmetry assay. Transcriptome sequencing was used to identify differentially expressed genes in HS-5 treated with different regimens. Western blotting (WB) was explored to validate the protein expression levels. Results: IFN-γ significantly reduced the viability of HS-5 cells at 1000ng/mL (relative viability: 0.738±0.162 vs. 1.000±0.142 for IFN-γ group and control group, P=0.026). The working concentrations were determined as 0.5 μg/mL and 4.0 μg/mL for EPAG, and 0.2 μg/mL and 4.0 μg/mL for AVA. EPAG and AVA alone did not significantly affect HS-5’s viability at working concentrations. After 48 hours of incubation with 1000ng/mL IFN-γ and 0.5 μg/mL EPAG, the viability of HS-5 cells was significantly elevated compared with the cells treated with IFN-γ alone (relative viability: 0.969±0.051 vs. 0.738±0.162, P=0.030). AVA did not rescue the viability of IFN-γ-treated HS-5 cells, and was thus not involved in the following cell apoptosis assay. Cell cytometry indicated that the proportion of late apoptotic/dead cells was significantly increased by IFN-γ (2.38%±0.09% in IFN-γ group vs. 1.35%±0.77% in control group, P=0.041), and was seemed to be improved after adding EPAG (1.89%±0.39% in EPAG+IFN-γ group vs. 2.38%±0.09% in IFN-γ group, P=0.053); however, adding EPAG did not rescue the increased early apoptosis induced by IFN-γ. Transcriptome sequencing and WB verification showed that ferroptosis key inhibitor GPX4 was down-regulated in IFN-γ treated cells compared with normal controls (relative expression level: 0.572±0.105 vs. 1.000±0.244, P<0.01), and up-regulated by adding EPAG (1.178±0.442 in EPAG+IFN-γ group vs. 0.572±0.105 in IFN-γ group, P<0.01). Summary/Conclusion: EPAG can rescue IFN-γ induced BM-MSC cell line’s late apoptosis/deaths, probably through down-regulation of ferroptosis inhibitor, which did not work for AVA. Keywords: Aplastic anemia, Bone marrow microenvironment, Mesenchymal stem cell
PB2463: PROTRACTED DIARRHEA FROM HIGH-DOSE MELPHALAN IN AUTOLOGOUS HEMATOPOIETIC TRANSPLANTATION: RESPONSE TO SHORT COURSE OF ORAL BUDESONIDE
Authors: Rammurti Kamble, Yuqi Zhang, Zimu Gong, Breanna Hinman, James Cox, George Carrum
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Approximately, 40% patients receiving high dose melphalan (HDM) develop grade III or IV diarrhea (CTCAE 5.0) that promptly improves upon neutrophilic engraftment. Persistence of grade III diarrhea beyond 24 hours post engraftment, though uncommon results in significant morbidity and prolongs hospitalization. Aims: To Explore role of oral Budesonide for patients with persistent diarrhea following high dose melphalan based chemotherapy conditioning Methods: Histopathologic finding of colonic crypt inflammation in a patient (first on table 1) led to utilization of short course of oral budesonide (BUD) resulting in rapid and sustained resolution of diarrhea. We herein document 5 such cases and discuss its role in reducing morbidity and duration of hospitalization. Persistent grade III diarrhea 24 hours after neutrophil engraftment defined protracted diarrhea from melphalan. Infectious workup including stool examination for salmonella, shigella, rotavirus, cryptosporidium, clostridium difficile were performed. Results: The median age of 5 patients was 64 (range, 44-73) years (Females=3, Males=2). A total of 3 patients with multiple myeloma received melphalan 200 mg/m2 while 1 with associated renal failure received Melphalan 140 mg/m2. One patient with Hodgkin’s lymphoma also received melphalan 140 mg/m2 (table 1). Median time to neutrophilic engraftment following autologous stem cell transplant (ASCT) was day +12 (range, 10-12) days. negative. Colonoscopy in one patient confirmed patchy crypt apoptosis and crypt abscess formation. Standard supportive care including antidiarrheals offered no improvement. Oral budesonide (BUD)was introduced at median of 2 (range, 1-11) days from engraftment. The median cumulative dose of BUD comprised 12 mg (range, 9-72 mg). Four patients had rapid resolution of diarrhea within 24 hours, while 5th patient improved in 7 days. Median duration of BUD was 2 (range, 1-7) days. Median time to discharge from BUD initiation was 2 days (range 1-7). An additional patient was excluded from analysis as his stool tested positive for rotavirus; he too promptly responded to BUD. Summary/Conclusion: In absence of systemic studies, we postulate that reduction in gut inflammation improves diarrhea. We do not think these diarrheas were related to autologous graft versus host disease. We did not observe any untoward effects of such short courses of BUD. Palifermin, a recombinant human keratinocyte growth factor is effective in reducing diarrhea of HDM. However, its cost is prohibitive. Oral BUD results in rapid resolution of lower GI toxicity of HDM and potentially lowers cost of hospitalization.Keywords: Autologous hematopoietic stem cell transplantation
P1313: LOW DOSE RITUXIMAB FOR PRE-EMPTIVE TREATMENT OF EPSTEIN BARR VIRUS REACTIVATION AFTER ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: A RETROSPECTIVE SINGLE-CENTER STUDY
Authors: Chen Mei, Yanling Ren, Jiejin Qian, Hongyan Tong
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Epstein–Barr Virus (EBV) reactivation and EBV-associated post-transplant lymphoproliferative disorders (PTLD) are common complication after allogenic hematopoietic stem cells transplantation (allo-HSCT). The preemptive treatment of EBV reactivations with the Rituximab (375 mg/m2) weekly have led to considerable improvements in outcomes, but may be associated with an increased long-term risk of infections. We performed a retrospective study of patients with EBV reactivations and PTLD receiving preemptive treatment with low dose Rituximab. Aims: The main objective was to evaluate the efficacy of low dose Rituximab for EBV reactivation after allo-HSCT. Methods: We retrospectively analyzed allo-HSCT patients with EBV reactivation and treated with low dose Rituximab in our hospital between March 2021 and December 2022. Only patients with detectable EBV-DNA and no symptoms were eligible for preemptive therapy. Patients with EBV-DNA >500 UI/ml have a reduction of immunosuppressive therapy if possible. Patients with persistent EBV-DNA >500 UI/ml or without possibility of reduction of immunosuppressive were treated preemptively with Rituximab (100 mg) weekly until EBV-DNA below 500 UI/ml. Results: We have included a total of 30 patients with EBV reactivation. The median age of patients was 37 (range, 16–65) years with 56.7% of male patients. Diagnoses were myeloid malignancies (53.3%) and lymphoid malignancies (46.7%). Donors were matched-related (3.3%) and haploidentical (96.7%) for the patients, respectively. Three patients (10.0%) underwent reduced-intensity conditioning regimen, while the remaining 27 patients (90.0%) received myeloablative conditioning regimen. Treatment with Rituximab was successful in 28/30 patients (93.3%). Two PTLD were diagnosed whereas EBV-DNA was decreased below 500 UI/ml. The median number of Rituximab infusions was 2 (range, 1–4). Summary/Conclusion: In this retrospective, monocentric study, the use of a low Rituximab dose (100 mg) for pre-emptive therapy of EBV reactivation post HSCT was efficient with a success rate over 93%. A prospective randomized multicentric trial with larger number of patients is needed to determine the best Rituximab dose. Keywords: Hematopoietic cell transplantation, EBV
PB2644: NOVEL GLOBAL FIBRINOLYSIS CAPACITY ASSAYS: THE NEXT STEP IN FIBRINOLYSIS SCREENING?
Authors: Anton Evenepoel, Anne Demulder, Laurence Rozen
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: Exploring fibrinolysis has always been time-consuming, difficult and incomplete because of a lack of easy available tests. The Lysis timer® (LT), a device developed by Biophen, is designed to determine the global fibrinolysis capacity (GFC) of patients. With the capacity to provide results in less than 1 hour. The GFC/LT tests the dissolution of a plasma clot, obtained by the addition of thrombin and calcium, in the presence of silica and a defined amount of exogenous tissue plasminogen activator (tPA). Aims: The aim of our project is to evaluate GFC/LT method in our laboratory. Methods: The validation evaluated the device’s analytical performance and the establishment of usual values. This evaluation includes the determination of practicability, precision and accuracy of the results (8 replicates performed on 5 days on 3 levels of quality controls), room temperature stability and validation of centrifugation protocols. Results were significant if P<0.05. Usual reference values were determined in different populations: adult (n = 61), pregnant persons (n = 29) and pediatric (n = 22). These values were compared to insert reference values and literature findings. Results: All performed tests attained the acceptance criteria (Table 1). The highest coefficient of variation (CV) and bias were respectively 6.1% and 7.8%. The bias of QC Hypofibrinolysis and QC Normal was statistically different form the target value; however, the obtained values were still in the acceptance range for these levels. While manufacturer room temperature stability is set at 2h, we found a stability up to 4h. To facilitate routine use, multiple centrifugations protocols were tested, the rapid 8’ 1500G protocol was comparable with the manufacturer proposed 15’ 2500G. Following usual values were found: [32’24”; 54’09”] in adults, [35’11”; 53’51”] in pregnant women and [31’55”; 57’:40”] in the pediatric population. These values are comparable with the reference values proposed by both the manufacturer as the literature. Summary/Conclusion: The Lysis Timer® shows promising results for the quick and easy screening of the fibrinolytic capacity in patients. The analytical evaluation reveals good and robust results. With minor changes of the protocol (rapid centrifugation), implementation in the routine flow should be possible. However further research is needed to establish correlation with existing fibrinolysis assays (euglobulin clot lysis time and thromboelastography) as well as the usage in different patient populations.Keywords: Hemostasis, Fibrinolysis, Assay
Health Digital Twins in Life Science and Health Care Innovation
Authors: Kaushik P. Venkatesh, Gabriel Brito, Maged N. Kamel Boulos
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Health digital twins (HDTs) are virtual representations of real individuals that can be used to simulate human physiology, disease, and drug effects. HDTs can be used to improve drug discovery and development by providing a data-driven approach to inform target selection, drug delivery, and design of clinical trials. HDTs also offer new applications into precision therapies and clinical decision making. The deployment of HDTs at scale could bring a precision approach to public health monitoring and intervention. Next steps include challenges such as addressing socioeconomic barriers and ensuring the representativeness of the technology based on the training and validation data sets. Governance and regulation of HDT technology are still in the early stages.
ESMO Expert Consensus Statements on the management of breast cancer during pregnancy (PrBC)
Authors: S. Loibl, H.A. Azim, T. Bachelot, P. Berveiller, A. Bosch, E. Cardonick, C. Denkert, M.J. Halaska, M. Hoeltzenbein, A.L.V. Johansson, C. Maggen, U.R. Markert, F. Peccatori, P. Poortmans, E. Saloustros, C. Saura, P. Schmid, E. Stamatakis, M. van den Heuvel-Eibrink, M. van Gerwen, V. Vandecaveye, G. Pentheroudakis, G. Curigliano, F. Amant
Journal: Annals of Oncology (2023)
CD39 inhibition and VISTA blockade may overcome radiotherapy resistance by targeting exhausted CD8+ T cells and immunosuppressive myeloid cells
Authors: Yuhan Zhang, Junyi Hu, Kai Ji, Shengpeng Jiang, Yang Dong, Lin Sun, Jun Wang, Guangyuan Hu, Dawei Chen, Ke Chen, Zhen Tao
Journal: Cell Reports Medicine (2023)

Although radiotherapy (RT) has achieved great success in the treatment of non-small cell lung cancer (NSCLC), local relapses still occur and abscopal effects are rarely seen even when it is combined with immune checkpoint blockers (ICBs). Here, we characterize the dynamic changes of tumor-infiltrating immune cells after RT in a therapy-resistant murine tumor model using single-cell transcriptomes and T cell receptor sequencing. At the early stage, the innate and adaptive immune systems are activated. At the late stage, however, the tumor immune microenvironment (TIME) shifts into immunosuppressive properties. Our study reveals that inhibition of CD39 combined with RT preferentially decreases the percentage of exhausted CD8+ T cells. Moreover, we find that the combination of V-domain immunoglobulin suppressor of T cell activation (VISTA) blockade and RT synergistically reduces immunosuppressive myeloid cells. Clinically, high VISTA expression is associated with poor prognosis in patients with NSCLC. Altogether, our data provide deep insight into acquired resistance to RT from an immune perspective and present rational combination strategies.
Novel Approaches to Immunomodulation for Solid Organ Transplantation
Authors: Irma Husain, Xunrong Luo
Journal: Annual Review of Medicine (2023)

Despite significant advances in the field of transplantation in the past two decades, current clinically available therapeutic options for immunomodulation remain fairly limited. The advent of calcineurin inhibitor–based immunosuppression has led to significant success in improving short-term graft survival; however, improvements in long-term graft survival have stalled. Solid organ transplantation provides a unique opportunity for immunomodulation of both the donor organ prior to implantation and the recipient post transplantation. Furthermore, therapies beyond targeting the adaptive immune system have the potential to ameliorate ischemic injury to the allograft and halt its aging process, augment its repair, and promote recipient immune tolerance. Other recent advances include expanding the donor pool by reducing organ discard, and bioengineering and genetically modifying organs from other species to generate transplantable organs. Therapies discussed here will likely be most impactful if individualized on the basis of specific donor and recipient considerations. Expected final online publication date for the Annual Review of Medicine, Volume 75 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Proactive and reactive roles of TGF-β in cancer
Authors: Nick A. Kuburich, Thiru Sabapathy, Breanna R. Demestichas, Joanna Joyce Maddela, Petra den Hollander, Sendurai A. Mani
Journal: Seminars in Cancer Biology (2023)

Cancer cells adapt to varying stress conditions to survive through plasticity. Stem cells exhibit a high degree of plasticity, allowing them to generate more stem cells or differentiate them into specialized cell types to contribute to tissue development, growth, and repair. Cancer cells can also exhibit plasticity and acquire properties that enhance their survival. TGF-β is an unrivaled growth factor exploited by cancer cells to gain plasticity. TGF-β-mediated signaling enables carcinoma cells to alter their epithelial and mesenchymal properties through epithelial-mesenchymal plasticity (EMP). However, TGF-β is a multifunctional cytokine; thus, the signaling by TGF-β can be detrimental or beneficial to cancer cells depending on the cellular context. Those cells that overcome the anti-tumor effect of TGF-β can induce epithelial-mesenchymal transition (EMT) to gain EMP benefits. EMP allows cancer cells to alter their cell properties and the tumor immune microenvironment (TIME), facilitating their survival. Due to the significant roles of TGF-β and EMP in carcinoma progression, it is essential to understand how TGF-β enables EMP and how cancer cells exploit this plasticity. This understanding will guide the development of effective TGF-β-targeting therapies that eliminate cancer cell plasticity.
Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes
Authors: Joseph T. Glessner, Mylarappa B. Ningappa, Kim A. Ngo, Maliha Zahid, Juhoon So, Brandon W. Higgs, Patrick M.A. Sleiman, Tejaswini Narayanan, Sarangarajan Ranganathan, Michael March, Krishna Prasadan, Courtney Vaccaro, Miguel Reyes-Mugica, Jeremy Velazquez, Claudia M. Salgado, Mo R. Ebrahimkhani, Lori Schmitt, Dhivyaa Rajasundaram, Morgan Paul, Renata Pellegrino, George K. Gittes, Dong Li, Xiang Wang, Jonathan Billings, Robert Squires, Chethan Ashokkumar, Khalid Sharif, Deirdre Kelly, Anil Dhawan, Simon Horslen, Cecilia W. Lo, Donghun Shin, Shankar Subramaniam, Hakon Hakonarson, Rakesh Sindhi
Journal: Journal of Hepatology (2023)

Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.
Biomedical applications of engineered heparin-based materials
Authors: Ehsan Nazarzadeh Zare, Danial Khorsandi, Atefeh Zarepour, Hulya Yilmaz, Tarun Agarwal, Sara Hooshmand, Reza Mohammadinejad, Fatma Ozdemir, Onur Sahin, Sevin Adiguzel, Haroon Khan, Ali Zarrabi, Esmaeel Sharifi, Arun Kumar, Ebrahim Mostafavi, Negar Hosseinzadeh Kouchehbaghi, Virgilio Mattoli, Feng Zhang, Vadim Jucaud, Alireza Hassani Najafabadi, Ali Khademhosseini
Journal: Bioactive Materials (2023)

Heparin is a negatively charged polysaccharide with various chain lengths and a hydrophilic backbone. Due to its fascinating chemical and physical properties, nontoxicity, biocompatibility, and biodegradability, heparin has been extensively used in different fields of medicine, such as cardiovascular and hematology. This review highlights recent and future advancements in designing materials based on heparin for various biomedical applications. The physicochemical and mechanical properties, biocompatibility, toxicity, and biodegradability of heparin are discussed. In addition, the applications of heparin-based materials in various biomedical fields, such as drug/gene delivery, tissue engineering, cancer therapy, and biosensors, are reviewed. Finally, challenges, opportunities, and future perspectives in preparing heparin-based materials are summarized.